Clomiphene is an active pharmaceutical ingredient used as ovulatory stimulant to treat ovulatory dysfunction and polycystic ovary syndrome.
Clomiphene has chemical name Ethanamine, 2-[4-(2-chloro-1,2-diphenylethenyl)phenoxy]-N,N-diethyl and it is a mixture of the geometric isomers trans-Clomiphene of chemical formula (I) and cis-Clomiphene of chemical formula (II):

The pharmaceutical products currently on the market containing Clomiphene, typically as monocitrate salt, comprise Clomiphene having the following composition: from 50% to 70% of trans-clomiphene and from 30% to 50% of cis-Clomiphene.
Trans-Clomiphene of chemical formula (I), also named Enclomiphene or E-Clomiphene, as monocitrate salt, is currently under evaluation in clinical phase III for the treatment of secondary hypergonadism. Moreover, it is also said that trans-Clomiphene could be potentially used for an adjuvant therapy in hypogonadal men with Type 2 diabetes.
U.S. Pat. No. 3,848,030, in examples 31 and 32, discloses a process for the resolution of the geometric isomers of Clomiphene through the preparation of salts with racemic binaphthyl-phosphoric acid.
In the later publication Acta Cryst. (1976), B32, pag. 291-293, the geometric isomery has been definitely established by single crystal X-Ray diffraction.
Finally, in the publication “Analytical profiles of drug substances and excipients”, vol. 25, (1998), page 85-121, in particular at page 99, it is stated that prior to 1976 the cis stereochemistry was assigned to the trans-isomer of Clomiphene (E-Chlomiphene), and only after the above publication on Acta Cryst. has the correct geometric isomery been definitively assigned.
These observations in the prior art have been confirmed by our experimentation. In particular, repeating the experiment 31 of U.S. Pat. No. 3,848,030, the trans-Clomiphene salt with racemic binaphthyl-phosphoric acid was isolated and not the salt with cis-Clomiphene as stated in said patent.
U.S. Pat. No. 2,914,563, in example 3, and the recent PCT application WO2014/031177, in example 1, disclose a process for the preparation of trans-Clomiphene citrate, containing from 30% to 50% of cis-Clomiphene, as citrate, by reaction of 1-p-(β-diethylaminoethoxy)phenyl]-1,2-diphenylethylene hydrochloride with N-chlorosuccinimmide in dry chloroform under reflux.
According to our experimental studies, these prior art methods for the preparation of Clomiphene and, in particular, trans-Clomiphene, suffer from drawbacks related to unknown impurities which can contaminate the final product Clomiphene.